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Int. J. Environ. Res. Public Health 2010, 7, 1366-1378; doi:10.3390/ijerph7041366 OPEN ACCESS

International Journal of Environmental Research and Public Health ISSN 1660-4601 www.mdpi.com/journal/ijerph Article

Alcohol and HCV Chronic Infection Are Risk Cofactors of Type 2 Diabetes Mellitus for Hepatocellular Carcinoma in Italy Massimiliano Balbi 1, Valter Donadon 1,*, Michela Ghersetti 1, Silvia Grazioli 1, Giovanni Della Valentina 1, Rita Gardenal 1, Maria Dal Mas 1, Pietro Casarin 1, Giorgio Zanette 2, Cesare Miranda 2 and Paolo Cimarosti 3 1

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Department of Medicine, Internal Medicine 3rd, Pordenone Hospital, Via Montereale 24, Pordenone 33170, Italy; E-Mails: [email protected] (M.B.); [email protected] (M.G.); [email protected] (S.G.); [email protected] (G.D.V.); [email protected] (R.G.); [email protected] (M.D.M.); [email protected] (P.C.) Diabetes Clinic, Pordenone Hospital, Via Montereale 24, Pordenone 33170, Italy; E-Mails: [email protected] (G.Z.); [email protected] (C.M.) Community Addictions Service, Pordenone Hospital, Via Montereale 24, Pordenone 33170, Italy; E-Mail: [email protected]

* Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +39-0434-399280; Fax: +39-0434-399559. Received: 3 December 2009; in revised form: 8 February 2010 / Accepted: 15 March 2010 / Published: 29 March 2010

Abstract: Type 2 diabetes mellitus (DM2) has been associated with hepatocellular carcinoma (HCC) development. To study this relationship, we enrolled 465 HCC patients compared with 618 Cirrhotic cases and 490 Controls. The prevalence of DM2 is significantly higher in HCC patients with an Odds Ratio of 3.12 versus Controls. In HCC cases with alcohol abuse, the frequency of DM2 is the highest. In our HCC patients, when HCV infection is associated with alcohol abuse, the liver cancer develops earlier. In addition, multivariate analysis shows that alcohol consumption is an independent risk factor for HCC more relevant than HCV infection. Keywords: Hepatocellular carcinoma; Type 2 diabetes mellitus; HCV infections; alcohol abuse

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1. Introduction Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related deaths [1]. In recent years, a significant increase in hepatocellular carcinoma incidence and mortality rates has been observed in developed countries, but the causes of this growth are only partially understood. Although the main risk factors for HCC are hepatitis C virus, hepatitis B virus (HBV) and chronic alcohol abuse, at least 25% of HCC cases do not have any known etiology, suggesting that further risk factors could be responsible for the increasing incidence of HCC. Diabetes mellitus has recently been proposed as a risk factor for HCC [2,3]. During the past two decades, the prevalence of diabetes mellitus, and in particular of type 2 diabetes mellitus, has dramatically increased in many countries, including Italy [4]. Sedentary lifestyles, excessive food consumption and obesity appear to be the main causes of the current diabetes mellitus epidemic in the western world [5]. Previous studies on the association between diabetes mellitus and liver diseases showed that type 2 diabetes mellitus appears to be a cause of non-alcoholic fatty liver disease (NAFLD) and that cirrhosis and hepatitis C virus infection increase the susceptibility to diabetes mellitus [6,7]. Moreover, conflicting results were reported on the association between diabetes mellitus and solid tumors, in particular HCC [3,8-12]. While earlier investigations did not report any association between diabetes mellitus and HCC, recent data clearly indicate that diabetes mellitus is a risk factor for HCC [13-15]. However, the precise relation between diabetes mellitus and chronic liver diseases still needs to be further investigated. Two recent studies have suggested a synergistic interaction in the HCC occurrence among heavy alcohol consumption, chronic viral hepatitis and diabetes mellitus in American blacks and whites [16,17]. The aims of our study are to provide a precise assessment on the effect of alcohol consumption and HCV infections, alone and as co-factors of diabetes mellitus, on the risk of HCC in Italian patients. 2. Methods 2.1. Ethics This work has been carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association. We performed a retrospective, case-control study on three groups of Caucasian individuals, attending the Liver Unit and Diabetic Clinic of 3rd Internal Medicine in the Pordenone General Hospital (Pordenone, Italy) from January 1994 to June 2006. The 3rd Internal Medicine of Pordenone Hospital is a tertiary referral centre for liver disease and diabetes mellitus. This study is a single centre investigation and all patients of the three groups studied were all afferent, directly diagnosed and followed-up in the 3rd Internal Medicine of Pordenone Hospital. A series of patients with HCC was compared with two different groups: one consisted of patients with liver cirrhosis (LC) and the other one, the Controls, included individuals who were treated in our

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Hospital for a wide spectrum of acute conditions. The demographic features of these groups are summarized in Table 1. Table 1. Characteristics of the HCC, LC and Control groups.

Sex Male n (%) Age years mean ±SD BMI kg/m2 mean ±SD Alcohol abuse n (%) DM2 n (%) HBV+ n (%) HCV+ n (%) Duration of type 2 diabetes months, mean ±SD Duration of cirrhosis Months, mean ±SD Child-Pugh score (A, B, C %)

HCC (n = 465) 364 (78.3) 68.5 ±8.9 25.2 ±3.1 141 (30.4) 145 (31.2) 20 (4.3) 177 (38.1)

LC (n = 618) 450 (72.8) 64.9 ±12.2 25.1 ±3.2 188 (30.5) 144 (23.3) 27 (4.4) 236 (38.3)

Controls (n = 490) 385 (78.6) 69.4 ±13.8 25.1 ±2.9 46 (9.5) 62 (12.7) 5 (1.1) 26 (5.3)

P NS1 NS1 NS1 NS2 400 ng/mL, computerized tomography scan and/or magnetic resonance imaging of the upper abdomen. Clinical data, biochemical parameters and the antidiabetic treatment were considered at the time of HCC diagnosis. 2.2.2. LC group We enrolled 618 patients with liver cirrhosis (LC), matched with the HCC cases by age (±5 years), gender, body mass index (BMI), transaminases, history of diabetes, prevalence of hepatitis B virus and hepatitis C virus infections, alcohol consumption and time of admission. These patients were admitted to our hospital for diagnosis, staging or therapy of liver cirrhosis. Clinical data, biochemical parameters and antidiabetic treatment were considered at the time of recruitment.

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According to Child’s classification of cirrhosis, patients were classified as follows: class A: 55.5%; B: 24.3% and C: 20.2%. In the cirrhotic patients, the presence of HCC was ruled out through ultrasound examinations, CT or MRI of the upper abdomen and AFP checks. 2.2.3. Control group From 28,740 in-patients of our region, 490 subjects matched with HCC and LC patients by age (±5 years), gender, BMI, history of diabetes and time of admission were recruited. Those who were admitted for malignancies, alcohol-related disease, viral liver disease and diabetes mellitus were excluded from our study, although comorbidity of these conditions was not considered as an exclusion criterion. Therefore, the primary diagnoses of admission were: heart failure (34.9%), hypertension (21.4%), chronic obstructive broncho-pneumopathies or pneumonia (16.5%), atrial fibrillation (7.8%), deep venous thrombosis (6.5%), fever of unknown origin (5.3%), benign tumors (4.1%), gastritis (3.5%). The Control group subjects are not matched with LC and HCC patients for HCV and HBV infection, alcohol consumption, diabetes mellitus history and antidiabetic treatment. In fact, our purpose was to select the Controls in order to be sure that they represent our region’s general population as regards to HCV, HBV infection, alcohol consumption and diabetes mellitus prevalence in subjects of the 60−75 years age group, which is the age interval in which the mean age of our HCC patients is located. Therefore, the prevalence for the following parameters, as total in the free living population of our region and in their age interval of 60−75 years, compared to those of the selected Controls, are the following:  HCV infection: 3.2% total and 5.0% in the age group of 60−75 years of the general population as regards to 5.3% of Controls in the present study;  HBV infection: 1.2 % in all the general population as to 1.68% in the age group of 60−75 years and 1.15 % in Controls;  Alcohol abuse: 4.5% in general population as to 9.7% in the 60−75 years age group and 9.5% in Controls;  Diabetes mellitus : 4.8% in the general population as regards to 12.4% in the age group of 60−75 years and 12.7% in Controls of this study [19-22]. 2.3. Data Collection The demographic, clinical and biochemical data of each patient were collected in a computerized database. Biochemical parameters were determined at the Pordenone Hospital central laboratory using standardized and validated methods. Hepatitis B surface antigen (HBsAg), anti-HBV surface antigen (anti-HBs), anti-HBV core antigen (anti-HBc), and hepatitis B e antigen (HBeAg) were determined using commercial assays (Abbott Diagnostic Division, Wiesbaden; Germany). Sera were also screened for antibodies against HCV (anti-HCV) using a third-generation micro particle enzyme immunoassay (AxSYM HCV version 3.0,

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Abbott Diagnostic Division). Positive samples were tested for anti-HCV using a third-generation line immunoassay (Immunogenetics, Gent, Belgium) and for serum HCV-RNA using the Roche Amplicor version 2.0 (Roche Molecular System, Pleasenton, CA). The diagnosis and clinical classification of diabetes mellitus were based on the guidelines of the American Diabetes Association [23,24]. In particular, the distinction between type 1 and 2 diabetes mellitus, was made according to the following clinical characteristics: age and modality of glucose intolerance onset, previous use of antidiabetic medications, occurrence of ketoacidosis, obesity and body fat distribution, concomitant autoimmunity, positive family history and HLA association, presence of micro- and macrovascular complications when diabetes was diagnosed. A trained nurse assessed the alcohol intake by interviewing the patients using a standard questionnaire. Total alcohol intake was evaluated retrospectively on the basis of a history of lifetime consumption, dividing the patient’s life into 10-years periods, and recorded as the average amount of ethanol (mL) ingested daily. Each subject was classified according to his/her maximum level of alcohol consumption for one or more decades in his/her lifetime in order to avoid underestimation of alcohol consumption in subjects with HCC and a history of alcoholic liver disease. Alcohol use was evaluated considering an average alcohol content in volume of 5% for beer (a can = 330 mL), 12% for wine (a glass = 125 mL), 18% for aperitifs, 30% for digestive alcoholic drinks and 40% for liqueurs (a measure = 40 mL). A glass of wine, a can of beer or a measure of superalcoholics contain about 16 g of ethanol. Alcohol abuse was defined as a daily consumption over 30 g for males and over 20 g for females. Average alcohol content was estimated in 5% for beer, 12% wine and 40% spirits [25]. 2.4. Statistical Analysis Normality tests were performed on all data. Parametric data are expressed as mean values ± standard deviation (SD). Data with multiple time points variables were analysed by the general model ANOVA. Post hoc multiple comparisons were performed using an LSD test when ANOVA testing was significant (P ≤ 0.05). To establish univariate associations among variables, the odds ratio (OR) with a confidence interval of 95% was calculated, using the simple analysis of the logistic regression. Multivariate logistic regression was used to assess the association of HCC with DM2 after adjusting for potentially confounding factors. Evaluating the association of DM2 with the risk of HCC using LC patients as the Control group, we considered sex, age, body mass index, HBV and HCV infection, alcohol abuse, ALT level. Using the Control group, potential confounders included only sex, age, BMI, and alcohol abuse. We examined the potential interaction effects between the independent risk factors on HCC risk. When assessing if the combined effect of two factors on HCC was greater than the sum of the individual effects, we used the Synergy Index (SI) method described by Rothman [26]. A value of SI equal to unity was interpreted as indicative of additivity, whereas a value greater than unity was indicative of superadditivity and synergism. All statistical analyses were performed using SAS v9.1 (SAS Institute Inc., Cary, NC, USA).

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3. Results Each subject with diabetes mellitus in the HCC and LC groups showed the clinical and metabolic characteristics of type 2 diabetes mellitus. Of note, none of our HCC or liver cirrhosis patients had type 1 diabetes mellitus. As shown in Table 2, the prevalence of DM2 was 31.2% in the HCC group, 23.3% in the LC group and 12.7% in the Controls. The prevalence of DM2 in the three groups were statistically different (P < 0.0001), with an OR of 3.12 (CI 2.2−4.4; P < 0.001) in HCC group versus Controls and an OR of 2.09 (CI 1.5−2.9; P < 0.001) in HCC versus LC cases. Etiology of the chronic liver disease, mean age at HCC diagnosis and DM2 prevalence in the HCC patients are summarized in Table 3. Notably, alcohol related HCC had a significantly higher prevalence of DM2 compared to the HCV-positive group of HCC (36.9% versus 26.5%; P = 0.048). Table 2. Frequency of type 2 diabetes mellitus in HCC, LC and control groups. Subjects (n) Total -HCC(465) Controls (490) - LC (618) Males - HCC (364) - Controls (385) - LC (450) Females - HCC (101) - Controls (105) - LC (168)

DM2-negative n (%)

DM2-positive n (%)

OR (95% CI)

P

320 (68.8) 428 (87.3) 474 (76.7)

145 (31.2) 62 (12.7) 144 (23.3)

3.12 (2.2-4.4)a 2.09 (1.5-2.9)c